Hydroxyl compounds and compositions for cholesterol management and related uses
The present invention relates to novel hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.
1. A compound of the formula I:
or a pharmaceutically acceptable salt, hydrate, solvate or mixture thereof, wherein:
(a) each occurrence of m is independently an integer ranging from 0 to 5;
(b) each occurrence of n is independently an integer ranging from 3 to 7;
(c) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of R 1 ,R 2 ,R 11 , and R 12 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl, wherein R 1 ,R 2 ,R 11 , and R 12 are not each simultaneously H; and
(e) each occurrence of Y 1 and Y 2 is independently (C 1 -C 6 )alkyl, OH, COOH, COOR 3 , SO 3 H,
wherein:
(i) Y 1 and Y 2 are not each simultaneously (C 1 -C 6 )alkyl;
(ii) R 3 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups,
(iii) each occurrence of R 4 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6 alkoxy, or phenyl groups; and
(iv) each occurrence of R 5 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
2. The compound of claim 1 , wherein each occurrence of Y 1 and Y 2 is independently OH, COOR 3 , or COOH.
3. The compound of claim 1 , wherein m is 0.
4. The compound of claim 1 , wherein m is 1.
5. The compound of claim 1 , wherein n is 4.
6. The compound of claim 1 , wherein n is 5.
7. The compound of claim 1 , wherein z is 0.
8. The compound of claim 1 , wherein z is 1.
9. The compound of claim 1 , wherein Y 1 is (C 1 -C 6 )alkyl and Y 2 is OH.
10. The compound of claim 1 , wherein Y 1 is methyl and Y 2 is OH.
11. A compound according to claim 1 wherein said compound has the structure:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
12. A compound according to claim 1 wherein said compound has the structure:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
13. A compound according to claim 1 wherein said compound has the structure:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
14. A compound according to claim 1 wherein said compound has the structure:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
15. A compound of structure:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , 15 , 11 , 12 , 13 , or 14 and a pharmaceutically acceptable vehicle, excipient, or diluent.
17. A pharmaceutical composition comprising a compound of claim 1 , 15 , 11 , 12 , 13 , or 14 and further comprising a second therapeutic agent.
18. A pharmaceutical composition comprising a compound of claim 1 , 11 , 12 , 13 , or 14 and a pharmaceutically acceptable vehicle, excipient, or diluent which is administered in combination with a statin.